Chronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis. It is a pressing clinical problem and a profound unmet medical need. A number of theories of emphysema pathogenesis have been proposed. The "protease/ antiprotease" hypothesis contends that the normal lung is protected by an "antiprotease shield" and that emphysema is caused by an increase in proteases and/or a decrease in antiproteases. It has been speculated that the Th1 inflammation in COPD is responsible for these alterations. More recently, structural cell apoptosis has been documented in emphysema. The mechanism(s) of Th1 induction of protease/ antiprotease alterations is poorly understood. Importantly, the mechanism(s) by which Th1 responses induce tissue injury and destruction, in the lung or other organs, have also not been defined. Our studies demonstrate that cigarette smoke (CS) induces emphysema via an IFN-y-dependent mechanism and that IFN-y causes emphysema via a novel cathepsin-mediated epithelial cell apoptosis/DNA injury (CMEA) pathway. They also demonstrated that CMEA participates in a positive feedback loop that augments inflammation and protease burden. We hypothesize that: (1) IFN-y plays a critical role in the pathogenesis of pulmonary emphysema. (2) IFN-y induces emphysema via a novel CMEA response that is induced by early growth response gene 1 (Egr-1) and the extrinsic and intrinsic apoptosis pathways. (3) CMEA plays a central role in a caspase-11 and caspase-1-dependent amplification loop that regulates tissue inflammation and protease burden. We will test this hypothesis and address the mechanisms of-Th1-induced tissue destruction with the following aims. Aim 1: Characterize the alterations in the IFN-y system and the role(s) of these alterations in the pathogenesis of CS and IFN-y-induced emphysema. Aim 2: Characterize the cathepsin system responses in CS-exposed and IFN-y Tg mice and their role(s) in the pathogenesis of pulmonary apoptosis, injury and emphysema. Aim 3: Define the roles of Egr-1, the extrinsic and intrinsic apoptosis pathways and terminal effector caspases in the pathogenesis of IFN-y and CS-Induced pulmonary apoptosis, injury and emphysema. Aim 4: Define the contribution of and mechanism by which CMEA regulates inflammation and protease burden in CS-exposed and IFN-y Tg mice.